Studies on Dinucleoside Polyphosphates

Some Intriguing Biochemical, Physiological, and Medical Aspects

抄録

Dinucleoside 5′, 5′′′-P^α, P^ω-polyphosphates have been found in all cells examined. So far, the only known specific enzyme that catalyzes the synthesis of these polyphosphates is GTP:GTP guanylyltransferase. This enzyme produces Gp₄G, Gp₃G, and various Np_3-4Gs. The adenylated counterparts, such as Ap₃A and Ap₄A, are synthesized by ligases, at least by some aminoacyl-tRNA synthetases. Ap₄A phosphorylase, firefly luciferase, acyl-CoA synthetase, and the DNA- and RNA-ligases are also able to produce Np_3-6As. By contrast, in addition to nonspecific enzymes such as phosphodiesterase I and nucleotide pyrophosphatase, there occur in all types of organism specific enzymes that degrade Np_3-6N's. These are the Np₃N′ hydrolases, the asymmetrically and symmetrically acting Np₄N′ hydrolases, the Np_nN′ phosphorylases, and recently described hydrolases that prefer Ap₆A and Ap₅A as substrates. Human Fhit protein, a putative tumor suppressor, behaves as a typical Np₃N′ hydrolase and is a member of the HIT (histidine triad) protein family. The human Np₄N′ hydrolase belongs to the MutT motif or Nudix (nucleoside diphosphate attached to “x”) hydrolase protein family. The level of Np_3-6N's in the cells increases dramatically under stress. It is suggested that these minor nucleotides act as both intra- and extracellular signalling molecules. Ap_nAs interact with purine receptors and affect vascular tone. Chemically synthesized analogues of Np_nN's help us to understand the mechanism of action of the enzymes mentioned, and some of them are candidates for drugs.